P587: COVALENT-101: A PHASE 1 STUDY OF BMF-219, A NOVEL ORAL IRREVERSIBLE MENIN INHIBITOR, IN PATIENTS WITH RELAPSED/REFRACTORY ACUTE LEUKEMIA, DIFFUSE LARGE B-CELL LYMPHOMA, AND MULTIPLE MYELOMA
Authors: F. Ravandi-Kashani, A. Kishtagari, H. Carraway, G. Schiller, E. Curran, B. Yadav, A. Cacovean, S. Morris, T. Butler, J. Lancet
Journal: HemaSphere (2022)

Background: Menin, a protein involved in transcriptional regulation, impacting cell cycle control, apoptosis, and DNA damage repair, plays a direct role in oncogenic signaling in multiple cancers. Inhibition of menin is therefore a novel approach to cancer treatment. Preclinical data of BMF-219, a highly selective, orally bioavailable, small-molecule irreversible inhibitor of menin, show sustained potent abrogation of menin-dependent oncogenic signaling in vitro and in vivo. BMF-219 exhibited a strong anti-proliferative effect on various menin-dependent acute myeloid leukemia (AML) cell lines, diffuse large B-cell lymphoma (DLBCL) cell lines representing Double/Triple Hit Lymphoma (DHL/THL) & Double Expressor Lymphoma (DEL), and multiple myeloma (MM) cell lines with diverse mutational backgrounds. BMF-219 also showed high potency ex vivo in patient samples from MLL-rearranged and NPM1-mutant AML, THL and MYC-amplified DLBCL, and bone marrow mononuclear cells from treatment-naive and relapsed/refractory (R/R) MM. Aims: COVALENT-101 (BF-MNN-101: NCT05153330) is a prospective, open-label, multi-cohort, non-randomized, multicenter Phase I study evaluating the safety, tolerability, and clinical activity of escalating doses of once daily oral BMF-219 in patients with R/R acute leukemia (AL), DLBCL and MM who have received standard therapy. The primary objective of the study is to determine independently for each cohort/indication, the optimal biological dose (OBD)/ recommended Phase 2 dose (RP2D) of BMF-219 oral monotherapy. Key secondary objectives include further evaluation of safety and tolerability, characterization of the pharmacodynamics and pharmacokinetics of BMF-219, and assessment of its antitumor activity based on best overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and time to progression (TTP) per disease-specific response criteria as assessed by the investigator. Food-effect studies will be performed in DLBCL and MM patients at certain dose levels. Methods: Utilizing an accelerated titration design, doses of BMF-219 will be escalated in single-subject cohorts independently for each indication until 1 subject experiences either a ≥ Grade 2 related adverse event or dose limiting toxicity (DLT). At that point, the cohort will switch to a classical "3 + 3" design. Treatment will continue in 28-day cycles until progression or intolerability. Expansion cohorts for each indication will enroll patients to obtain further safety and efficacy data. Patients with R/R AL, R/R DLBLC who received ≥ 2 but ≤ 5 therapies, and R/R MM who received ≥ 3 therapies and have either failed or are ineligible for any standard therapies are eligible. Patients must have ECOG PS ≤ 2, and adequate organ function. Key exclusion criteria include known CNS disease involvement, prior menin inhibitor therapy, and clinically significant cardiovascular disease. Results: The study is ongoing. Summary/Conclusion: The enrollment commenced in January 2022.